Process for preparing 1-(6-methylpyridin-3-yl)-2-[4-methylsulphonyl)-phenyl]ethanone

ABSTRACT

A five-step process for preparing 1-(6-methylpyridin-3-yl)-2-[4-methylsulfonyl)phenyl]ethanone of formula (I):                    
     The process involves the following steps: (a) 4-(methylthio)benzyl alcohol is converted into 4-(methylthio)benzyl chloride; (b) 4-(methylthio)benzyl chloride is converted with an alkali metal cyanide into 4-(methylthio)phenylacetonitrile; (c) 4-(methylthio)phenylacetonitrile is condensed with a 6-methyinicotinic ester to give 3-[2-(2-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine; (d) 3-[2-(4-(methylthio)phenyl-2-cyanoacetyl](6-methyl)pyridine is hydrolyzed and decarboxylated under acidic conditions to give 3-[2-(4-(methylthio)-phenyl)acetyl](6-methyl)pyridine is hydrolyzed and decarboxylated under acidic conditions to give 3-[2-(4-(methylthio)phenyl)acetyl(6-methyl)pyridine; and (e) 3-[2(4-(methylthio)phenyl)acetyl](6-methyl)pyridine is oxidized to give the end product. The compound of formula (I) is an intermediate for preparing COX-2 inhibitors, pharmaceutically active compounds having analgesic and antiinflammatory action.

This is a 371 PCT/EP00/06825, filed on Jul. 17, 2000, that has prioritybenefit of European Patent Application 9911466.1, filed on Jul. 27,1999, and of U.S. Provisional Application 60/186,680, filed on Mar. 30,2000.

The invention encompasses a novel process for preparing1-(6-methylpyridin-3-yl)-2-[(4-(methyl-sulphonyl)phenyl]ethanone of theformula:

1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)-phenyl]ethanone is animportant intermediate for preparing so-called COX-2 inhibitors,pharmaceutically active compounds having analgesic and antiinflammatoryaction (R. S. Friesen et al., Bioorganic & Medicinal Chemistry Letters 8(1998) 2777-2782; WO 98/03484).

The object of the invention is to provide a technically feasible proessfor preparing the intermediate for the formula I.

The object is achieved by the novel process according to the invention.

The process according to the invention is characterized by five steps,where,

in the first step a), 4-(methylthio,benzyl alcohol is converted withhydrochloric acid into 4-(methylthio)benzyl chloride,

in the second step b), 4-(methylthio)benzyl chloride is converted withan alkali metal cyanide into 4-(methyl-thio)phenylacetonitrile,

in the third step c), 4-(methylthio)phenylacetonitrile is condensed witha 6-methylnicotinic ester to give3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)-pyridine of theformula:

in the fourth step d),3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine ishydrolysed and decarboxylated under acidic conditions to give3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine of the formula:

and, in the last step e),3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine is oxidized to givethe end product.

Step a:

The chlorination of 4-(methylthio)benzyl alcohol to 4-(methylthio)benzylchloride is carried out using hydrochloric acid, advantageously usingconcentrated hydrochloric acid, at a temperature of from 10° C. to 40°C.

The reaction is usually carried out in an organic solvent,advantageously in a water-immiscible solvent, such as, for example, intoluene.

Typically, the chlorination takes about 1 h to 4 h. The4-(methylthio)benzyl chloride can be obtained in a simple manner byneutralizing the organic phase and removing the solvent. Furtherpurification can be achieved by distillation.

Step b:

The cyanidation of 4-(methylthio)benzyl chloride is carried out using analkali metal cyanide, advantageously in the presence of a phase transfercatalyst. Suitable alkali metal cyanides are sodium cyanide or potassiumcyanide. The phase transfer catalysts which can be chosen are known inthe art. Suitable are tetraalkylammonium halides, such as, for example,tetra-n-butylammonium chloride or tetra-n-butylammonium bromide. Ingeneral, the reaction is carried out in the presence of awater-immiscible solvent, such as, for example, toluene; if appropriate,water can be added. The reaction temperature is advantageously from 60°C. to 100° C. After a reaction time of 1 h to 6 h, the product can beisolated in a simple manner from the organic phase by removing thesolvent. Further purification of the product can be achieved byrecrystallization from, for example, diisopropyl ether.

Step c:

In the third step, ((methylthio)phenyl)aceto-nitrile is condensed with a6-methylnicotinic ester to give3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl]-(6-methyl)pyridine of theformula:

The condensation is advantageously carried out in the presence of analkali metal alkoxide, at a temperature between 60° C. and 110° C.Suitable alkali metal alkoxides are, for example, sodium methoxide orpotassium tert-butoxide. The reaction is advantageously carried out inthe presence of a lower alcohol or an aromatic hydrocarbon as solvent.After the condensation, the3-[2-(4-(methyl-thio)phenyl)-2-cyanoacetyl](6-methyl)pyridine can beobtained, for example, by adding the reaction mixture to cold water andprecipitating the product from the aqueous phase by acidifying itslightly.

Step d:

Hydrolysis and decarboxylation to give3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine of the formula:

are carried out under acidic conditions. Suitable acids are hydrochloricacid, phosphoric acid or mixtures of acetic acid with a mineral acid.Advantageously, a mixture of acetic acid and a mineral acid is employed,at a temperature of from 50° C. to 115° C. Particular preference isgiven to mixtures of acetic acid with concentrated hydrochloric acid ormixtures of acetic acid with concentrated sulphuric acid. Ifappropriate, a certain amount of water can be added to the mixtures.Good results were obtained using mixtures of acetic acid/concentratedhydrochloric acid 1:3 or acetic acid/concentrated sulphuric acid/water1:1:1. After a reaction time of about 1 h to 20 h, the mixture can beneutralized using, for example, an aqueous ammonia solution, as a resultof which the product precipitates out and can be isolated in a simplemanner.

Step e:

Oxidation of 3-[2-(4-(methylthio)phenyl)-acetyl](6-methyl)pyridine tothe end product is advantageously carried out using hydrogen peroxide inthe presence of an alkali metal tungstate, at a temperature of from 10°C. to 40° C., preferably at about 20° C. A particularly suitable alkalimetal tungstate is sodium tungstate of the formula Na₄WO 0.2H₄O. Thealkali metal tungstate is generally employed in catalytic amounts offrom 0.5 mol % to 20 mol %, based on the3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine used. The reactionis advantageously carried out in the presence of a lower alcohol assolvent. After a reaction time of about 1 h to 6 h, the end product canbe precipitated out by addition of water and then be isolated withoutany problems.

EXAMPLES Preparation of 4-(methylthio)benzyl chloride

Under an atmosphere of nitrogen, 78.7 g (500 mmo)l [sic] of4-(methylthio)benzyl alcohol were dissolved in 154.5 g of toluene. 131.6g, (1.3 mol) of conc. HCl were added, and the mixture was stirred at20-25° C. for 30 min. After 2 h (no starting material left according toTLC), the reaction mixture was diluted with 349 g of toluene and theaqueous phase was separated off. The organic phase was neutralized using14.0 g of NaHCO₂ and, after 15 min, filtered, and the solvent wasevaporated. The residue that remained consisted of 107.4 g of a yellowoil with toluene, corresponding to a yield of >95% (according to NMR).

¹H-NMR (CDCl₃):

7.30 (2H,d);

7.22 (2H,d),

4.55 (2H, s);

2.47 (3H, s).

¹H-NMR (DMSO):

7.37 (2H,d);

7.25 (2H, d);

4.73 (2H,d);

2.47 (3H,s).

Preparation of 4-(methylthio)phenylacetonitrile

Under an atmosphere of nitrogen, 25.9 g (150 mmol) of4-(methylthio)benzyl chloride were dissolved in 45.5 g of toluene. 9.29g (180 mmol) of sodium cyanide, 0.92 g (2.9 mmol) of tetrabutylammoniumchloride and 14.4 g of water were then added. The mixture was stirred at80-85° C. for 2 h. The reaction mixture was admixed with 30 g of tolueneand 45 g of water, the aqueous phase was decanted off and the organicphase was concentrated. This gave a residue of 24.6 g of the titleproduct in a yield of >95% (according to NMR) in the form of a pinksolid.

¹H-NMR (CDCl₃):

7.25 (4H,m)

3.70 (2H,s);

2.47 (3H,s).

Preparation of3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine

Under an atmosphere of nitrogen, a mixture of 38.5 g (250 mmol) of ethyl6-methylnicotinate, 29.9 g (500 mmol) of sodium methoxide (90.5%) and300 ml of toluene was added, at 85-90° C. and over the course of 30 min,to a solution of 47.3 g (250 mmol) of 4-(methylthio)phenylacetonitrilein 75 ml of toluene. This mixture was stirred under reflux for 14 h,then distilled until the overhead temperature exceeded 110° C. and keptat reflux for another 6 h. The reaction mixture was poured into 500 g ofice water, the organic phase was decanted off and the aqueous phase wasextracted with 3×100 ml of toluene. The aqueous phase was acidified topH 6.0 using conc. HCl. The resulting yellow-beige suspension wasfiltered and the residue was washed with water and dried. This gave 53.9g (76%) of the title product in the form of a yellow solid.

¹H-NMR (CDCl₃):

9.00 (1H,s);

8.10 (1H,d);

7.3 (5H,m);

5.45 (1H,s);

2.60 (3Hs);

2.45 (3H,s).

Preparation of 3-[2-(4-(methylthio)phenyl)acetyl]-(6-methyl)pyridine

A mixture of 8.0 g (28 mmol) of3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine, 20 ml ofacetic acid and 60 ml of concentrated hydrochloric acid was heated at95° C. to 100° C. for 1.5 h. The orange solution was cooled and adjustedto pH 10 using concentrated ammonia solution. The resulting yellow-beigesuspension was filtered and the residue was washed with water and dried.This gave 5.35 g (74%) of the title product in the form of a yellowsolid.

¹H-NMR (CDCl₃):

9.10 (1H,s);

8.15 (1H,d);

7.2 (5H,m);

4.21 (2H,s);

2.61 (3H,s);

2.45 (3H,s).

Preparation of1-(6-methylpyridin-3-yl)-2-[(4-(methyl-sulphonyl)phenyl]ethanone

Under an atmosphere of nitrogen, a suspension of 8.9 g (34.5 mmol) of3-[2-(4-(methylthio)phenyl)-acetyl](6-methyl)pyridine in 90 ml ofmethanol was heated to 55° C. and adjusted to pH 4.5 using 2 N sulphuricacid. An aqueous solution of 0.22 g (0.7 mmol) of sodium tungstate in 7ml of water was then added. At 55° C., 10 mol of hydrogen peroxide werethen added over the course of 1 h, and the mixture was then cooled toroom temperature and filtered. The slightly beige filtration residue waswashed using 2 ×30 ml of a mixture of water/isopropanol 2:1 and 2 ×30 mlof water and then dried under reduced pressure at room temperature. Thisgave 7.43 g of the title product in a yield of 75%.

¹H-NMR (CDCl₃):

9.15 (1H,s);

8.18 (1H,d);

7.92 (2H,d);

7.47 (2H,d);

7.30 (1H,d);

4.39 (2H,s);

3.04 (3H,s);

2.63 (3H,s).

What is claimed is:
 1. A process for preparing1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of theformula:

comprising: in first step (a), converting 4-(methylthio)benzyl alcoholinto 4-(methylthio)benzyl chloride, in second step (b), converting the4-(methylthio)benzyl chloride with an alkali metal cyanide into4-(methylthio)phenylacetonitrile, in third step (c), condensing the4-(methylthio)phenylacetonitrile with a 6-methylnicotinic ester to give3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)-pyridine of theformula:

in fourth step (d), hydrolyzing and decarboxylating the3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine underacidic conditions to give3-{2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine of the formula:

and, in last step (e), oxidizing the3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)-pyridine to give the endproduct.
 2. The process according to claim 1, wherein the reaction instep (a) is carried out at a temperature of from 10 to 40° C. and in anorganic solvent.
 3. The process according to claim 1, wherein thereaction in step (b) is carried out in the presence of a phase transfercatalyst.
 4. The process according to claim 3, wherein the reaction instep (b) is carried out at a temperature of from 60 to 100° C.
 5. Theprocess according to claim 3, wherein the condensation in step (c) iscarried out in the presence of an alkali metal alkoxide at a temperaturebetween 60 and 110° C.
 6. The process according to claim 4, wherein thehydrolysis and decarboxylation in step (d) is carried out using amixture of acetic acid and a mineral, at a temperature of from 50 to115° C.
 7. The process according to claim 6, wherein the oxidation instep (e) is carried out using hydrogen peroxide in the presence of analkali metal tungstate, at a temperature of from 10 to 40° C.
 8. Theprocess according to claim 1, wherein the reaction in step (b) iscarried out in the presence of a phase transfer catalyst.
 9. The processaccording to claim 1, wherein the reaction in step (b) is carried out ata temperature of from 60 to 100° C.
 10. The process according to claim1, wherein the condensation in step (c) is carried out in the presenceof an alkali metal alkoxide at a temperature between 60 and 110° C. 11.The process according to claim 1, wherein the hydrolysis anddecarboxylation in step (d) is carried out using a mixture of aceticacid and a mineral acid, at a temperature of from 50 to 115° C.
 12. Theprocess according to claim 1, wherein the oxidation in step (e) iscarried out using hydrogen peroxide in the presence of an alkali metaltungstate, at a temperature of from 10 to 40° C.